Fuchs corneal dystrophy (FCD) is a degenerative disorder of the corneal endothelium characterized by the formation of guttae, protrusions of the underlying collagen-rich extracellular matrix known as Descemets membrane. The average age of onset is 50, and patients typically reach end stage disease in their 60's and 70's, by which time guttae cover most of the cornea and ion transport functions of the endothelium are severely compromised. FCD is a common condition, with 4% of the population over age 40 affected. Despite the health and socioeconomic impact of the disorder, knowledge of the underlying mechanism and genetic load is sparse, with the only available treatment being corneal transplant surgery. This is the first competing renewal of a three year award, in which we will extend our previous clinical and genetic studies to a) expand our understanding of the clinical presentation and progression of FCD; b) identify its underlying genetic causes; and c) begin developing in vitro and in vivo models for FCD mutations. Our work consists of three specific aims that draw from the strengths of an interdisciplinary team. First, we will expand our patient collection and quantitatively document progression in families linked to known FCD loci (including two novel loci uncovered by our group in the past year). Second, taking advantage of our unique cohort, which is enriched for large, multigenerational families, we will identify novel genes for FCD using a combination of traditional genetics tools and exon capture coupled to next generation resequencing. Finally, we will extend on our recent discovery of familial loss of function mutations in TCF8 in late-onset FCD families, to generate in vitro and in vivo models of the disorder as a means of understanding its cellular basis. Completion of these studies will enhance significantly the understanding of the genetic basis of this common disorder, offer important new insights into its pathomechanism, and provide critical measures for establishing disease presentation and progression rates, which will be necessary for patient management and for the design of novel therapeutic paradigms.